This invention relates to novel compositions of matter containing optically pure (R,R)-formoterol. These compositions possess potent, long-lasting bronchodilating activity as β-adrenergic agonists while avoiding or reducing adverse effects, including but not limited to muscle tremor and tachycardia, as well as avoiding or reducing the development of tolerance or hypersensitivity on repeated administration. The compositions also provide an improved duration of action.
This invention also relates to methods of treating asthma, bronchitis, emphysema, bronchospasms, and other ailments in patients with obstructive airway or allergic disorders, while avoiding adverse effects, development of tolerance or hypersensitivity on repeated administration or a limited pattern of bronchial distribution when administered by inhalation.
The active compound of these compositions and methods is an optical isomer of formoterol, which is described in Ida, “Arzneim,” Forsch., 26:839-842 and 1337-1340 (1976) and in U.S. Pat. No. 3,994,974. Chemically, the active compound is N-hydroxy-5-(1-hydroxy-2-[(2-(4-methoxyphenyl)methylethyl]amino]ethyl]phenylformamide, which exists as two enantiomeric pairs of diastereomers. Of these, the R,R diastereomer is the most active and, when substantially optically pure, is hereinafter referred to as (R,R) formoterol. Formoterol is available commercially only as a racemic diastereomer: (R,R) and (S,S) in a 1:1 ratio, which is also the enantiomeric mixture referred to by the generic name formoterol. The racemic mixture of (±) formoterol that is commercially available for administration is a dihydrate of the fumarate salt.
When two chiral centers occur in the same molecule, each of them can exist in two possible configurations, thus giving rise to four combinations: (R,R); (S,S); (R,S); and (S,R). The enantiomeric pair (R,R) and (S,S) are mirror images of each other and therefore share chemical properties and melting points. Similarly, (R,S) and (S,R) are an enantiomeric pair. The mirror images of (R,R) and (S,S) are not, however, superimposable on (R,S) and (S,R). The relationship between these two groups is called diastereomeric, and (R,R) is a diastereomer of (R,S). Due to its two chiral centers, formoterol falls into this category.
Adrenergic or sympathomimetic drugs are so called because they are understood to exert their effect through their action on the body's adrenergic receptors of which there are three functionally divided types: α, β1 and β2 receptors.
On the basis of their interaction with these three receptor types, adrenergic or sympathomimetic drugs are in turn classified into three groups:
1.1 Non-selective sympathomimetic drugs;
1.2 Non-selective β sympathomimetic drugs; and
1.3 Selective β2 sympathomimetic bronchodilator drugs.
Drugs of group 1.1 exert both α and β sympathomimetic effects. This class of drugs includes the substances adrenaline and ephedrine. Both adrenaline and ephedrine are known clinically as bronchodilators. Though adrenaline, despite side effects induced by its α-sympathomimetic properties, is still used by some practitioners for the treatment of acute asthma, both drugs have largely been replaced for asthma therapy.
The drugs of group 1.2 have both β1 and β2 sympathomimetic activity but virtually no α-sympathomimetic activity. Of the group 1.2 drugs, isoprenaline is the best known representative. Isoprenaline differs from the drugs of group 1.3 in its faster onset but shorter duration of action and in its cardiac stimulating effects which result largely from its β1 activity. Though isoprenaline was previously extensively used for bronchodilator therapy in asthma, its use today has become clinically restricted. It is believed that a rise in the rate of asthma deaths in the UK in the 1960's was associated with isoprenaline usage, and this has resulted in a discontinuation in its clinical application.
The selective β2 sympathomimetic bronchodilator drugs of group 1.3 (hereinafter referred to collectively as “Group 1.3 drugs”) act, as their name implies, selectively on β2 adrenergic receptors. The Group 1.3 drugs include for example, the drug substances terbutaline, albuterol, fenoterol, isoetharine, metaproterenol and, more recently, the so-called “long acting selective β2 sympathomimetic bronchodilator drug substances”—formoterol, bambuterol and salmeterol. All of the above recited Group 1.3 drugs are commercially available and clinically used, generally in a pharmaceutically acceptable salt form, such as, e.,g., as the sulphate, hydrobromide, hydrochloride, fumarate or methanesulfonate or, where appropriate, one or other of the hydrate forms thereof.
Group 1.3 drugs characteristically contain as part of their structure an ethanolamine or a 2-aminoethanol moiety of formula I 
wherein R1 is an aromatic group: commonly 3,4 or 3,5-dihydroxyphenyl or 4-hydroxy-3-hydroxymethylphenyl, or, in the case of formoterol, 3-formylamino-4-hydroxyphenyl.
R2 and R3 are commonly H.
Since the formula I moiety comprises at least 1 asymmetric carbon atom (C-1 in formula I), all of the Group 1.3 drugs exist in optically active isomeric forms, with the chiral carbon atom having either the (R) or (S) configuration [as designated using the Cahn-Ingold-Prelog system (Angew, Chem. Intern. Ed. 5, 385-415(1966)]. When the C-1 carbon atom is the sole asymmetric carbon atom present in the structure, Group 1.3 drugs will exist as individual (R) or (S) enantiomers or in the racemic [(R,S)] form, i.e., as a 50:50 mixture of the (R) and (S) enantiomers.
Individual Group 1.3 drugs in which R2 is other than H, or in which the remainder of the molecule includes an asymmetric carbon atom (formoterol, e.g.) exist in a variety of isomeric forms: (a) in individual (R,R), (S,S), (R,S) and (S,R) isomeric forms; (b) as racemic (RS,RS) and (RS,SR) mixtures comprising the (R,R) with (S,S) and (R,S) with (S,R) enantiomeric pairs; as well as (c) in the form of diastereomeric mixtures comprising all four isomeric forms.
The Group 1.3 drugs can be administered orally, parenterally or most commonly, by inhalation, e.g. using nebulizers or metered aerosol devices or as inhaled powders. Inhalation of Group 1.3 drugs presently represents the mainstay of bronchodilator therapy for the treatment of asthma of all grades of severity.
The duration of bronchodilation induced by the majority of Group 1.3 drugs is relatively short and they are employed to relieve asthma attack as and when it occurs. As indicated above, however, the more recently introduced Group 1.3 drugs, such as formoterol, are characterized by their longer duration of action and hence an apparent reduced frequency of dosaging is required.
Although the Group 1.3 drugs are effective and generally seem to be well tolerated, their safety, especially at high dosages, has been questioned over many years and numerous reports have appeared on the adverse effects of Group 1.3 drug therapy (see, e.g., Paterson et al., American Review of Respiratory Disease, 120:844-1187 (1979), especially at page 1165 et seq.). More recently, from New Zealand, where a continuing increase in asthma death has been recorded, two case control studies reported in The Lancet have linked an increase in asthma mortality to the use of the Group 1.3 drug, fenoterol; see, esp., Editorial “β2 agonists in asthma: relief, prevention, morbidity”, Lancet, 336:1411-1412 (1990).
A subsequently reported Canadian study found that the use of inhaled Group 1.3 drugs, principally fenoterol and albuterol, is associated with “an increased risk of the combined outcome of fatal and near-fatal asthma, as well as of death from asthma alone.” Spitzer et al., New England J. Med., 326:501-506 (1992); and related Editorial, page 560.
Various possible explanations for observed episodes of increased airway obstruction, arterial hypoxaemia or “anomalous” or “paradoxical” bronchospasm, as well as increased morbidity associated with Group 1.3 drug usage, in particular long term/high dose usage, have been proposed. For example, reactive myogenic tone, increased inflammatory burden, adrenoceptor tachyphylaxis and induction of airway hyperreactivity, as well as the involvement of spasmogenic drug metabolic products or long term influence of aerosol spray propellants (see, e.g., Paterson et al. loc. cit. and Morley et al., Eur. Respir. J., 3:1-5 (1990).
There is mounting concern within the medical profession as to the potential dangers of Group 1.3 drug usage in asthma therapy. To quote the Lancet editorial already referred to:                “These studies raise serious question about the use of β2 agonists (i.e., Group 1.3 drugs). The findings of Sears et al. could be interpreted as supporting the current trend towards earlier use of corticosteroids and other preventers of inflammation [for asthma therapy] rather than perseverance with an escalating bronchodilator regimen. The findings of the Nottingham and Dunedin groups also indicate that there is some way to go before long acting β2 agonist preparations such as salmeterol and formoterol can be unreservedly recommended for routine use in the management of asthma. There seem to be clear advantages of compliance and possibly of anti-inflammatory activity associated with such agents, but the potential for adverse effects cannot be ignored. Clinicians, researchers and pharmaceutical companies must now attempt to redefine the use of β2 agonists in asthma.” [Emphasis added.]        
Equally, there has been an evident inability or reluctance to conceive of any problem in relation to Group 1.3 drug therapy as being inherent in Group 1.3 drugs themselves or as hitherto employed: cf. the following, taken from the previously cited editorial in the New England Journal of Medicine.                 “Although . . . too much reliance is placed on beta-agonists (Group 1.3 drugs], it is difficult to believe that the problem is related directly to the more regular use of inhaled beta-agonists.”        
While the suitability, in particular of high dose or long-term, Group 1.3 drug therapy has long been a subject of debate, the practice of administering drugs of this group as racemic mixtures has continued. This practice has been accepted by drug registration authorities world-wide and even the most recently introduced of the Group 1.3 drugs have been developed for clinical use as racemic mixtures. This practice is based upon the assumption or understanding that the non-bronchodilator component of the racemic mixture, i.e., the bronchodilatorily-less or inactive enantiomer (distomer) is devoid of any relevant drug effect and can thus be administered together with the bronchodilatorily-active isomer (eutomer) essentially as inactive ballast and without risk to the patient.
The teachings of the present invention thus stands in stark opposition to long, widely established and continuing practice, and runs contrary to the wisdom of the art.
As the Group 1.3 drugs clearly offer a very considerable potential benefit for bronchodilator usage in asthma, the need to find a means of avoiding, ameliorating or restricting any disadvantages inherent in their use is urgent and crucial. By meeting this need, the present invention may be anticipated to bring immeasurable benefit both to the medical profession, as well as to the population of asthma sufferers.
Formoterol, which is the subject of the present invention, is currently only available as a racemic mixture of the (R,R) and (S,S) diastereomers. Trofast et al., Chirality, 3:443-450 (1991) have described the preparation of each of the substantially pure isomers, and they have concluded that “[s]ince the (S,S) enantiomer is practically inactive, there is from this point of view no reason for its removal from the racemate in pharmaceutical preparations . . . ”.
Formoterol's primary use is as a long-acting bronchodilator for the relief of reversible bronchospasm in patients with obstructive airway disease such as asthma, bronchitis and emphysema.
Asthma, bronchitis and emphysema are known as Chronic Obstructive Pulmonary Disease, or COPD. COPD is characterized as generalized airways obstruction, particularly of small airways, associated with varying degrees of symptoms of chronic bronchitis, asthma, and emphysema. The term COPD was introduced because these conditions often coexist, and it may be difficult in an individual case to decide which is the major condition producing the obstruction.
Airways obstruction is defined as an increased resistance to airflow during forced expiration. It may result from narrowing or obliteration of airways secondary to intrinsic airways disease; from excessive collapse of airways during a forced expiration secondary to pulmonary emphysema; from bronchospasm as in asthma; or may be due to a combination of these factors. Although obstruction of large airways may occur in all these disorders, particularly in asthma, patients with severe COPD characteristically have major abnormalities in their small airways, namely those less than 2 mm internal diameter, and much of their airways obstruction is situated in this zone. The airways obstruction is irreversible except for that which can be ascribed to asthma.
Asthma is a reversible obstructive lung disorder characterized by increased responsiveness of the airways. Asthma can occur secondarily to a variety of stimuli. The underlying mechanisms are unknown, but inherited or acquired imbalance of adrenergic and cholinergic control of airways diameter has been implicated. Persons manifesting such imbalance have hyperactive bronchi and, even without symptoms, bronchoconstriction may be present. Overt asthma attacks may occur when such persons are subjected to various stresses, such as viral respiratory infection, exercise, emotional upset, nonspecific factors, such as changes in barometric pressure or temperature, inhalation of cold air or irritants, such as gasoline fumes, fresh paint and noxious odors, or cigarette smoke, exposure to specific allergens, as well as the ingestion of aspirin or sulfites in sensitive individuals. Psychologic factors may also aggravate an asthmatic attack but are not assigned a primary etiologic role.
Persons whose asthma is precipitated by allergens (most commonly airborne pollens and molds, house dust and animal dander) and whose symptoms are IgE-mediated, are said to have allergic or “extrinsic” asthma. They account for about 10 to 20% of adult asthmatics; in another 30 to 50%, symptomatic episodes seem to be triggered by non-allergenic factors, such as, for example, infection, irritants and emotional factors, and these patients are said to have non-allergic or “intrinsic” asthma. In many persons, both allergenic and non-allergenic factors are significant. While allergies are said to be a more important factor in children than in adults, the evidence is inconclusive.
Chronic bronchitis (unqualified) is a condition associated with prolonged exposure to non-specified bronchial irritants and accompanied by mucus hypersecretion and certain structural changes in the bronchi. Usually associated with cigarette smoking, it is characterized clinically by chronic productive cough. The term chronic obstructive bronchitis is used when chronic bronchitis is associated with extensive abnormalities of the small airways leading to clinically significant airways obstruction.
Pulmonary emphysema is enlargement of the air spaces distal to terminal non-respiratory bronchioles, accompanied by destructive changes of the alveolar walls. The term chronic obstructive emphysema is used when airways obstruction is also present and where it is clear that the major features of the disease can be explained by emphysematous changes in the lungs.
Many of the β2 agonists cause somewhat similar adverse effects. These adverse effects include but are not limited to, the central nervous system symptoms such as hand tremors, muscle tremors, nervousness, dizziness, headache and drowsiness; respiratory side effects such as dyspnea, wheezing, drying or irritation of the oropharynx, coughing, chest pain and chest discomfort; cardiovascular effects such as palpitations, increased heart rate, and tachycardia. According to Trofast et al. (previously cited), (R,R) formoterol is primarily a chronotropic agent in vitro with inotropic effects showing up at higher concentrations. The chronotropic effects are reported at concentrations that are higher than those at which relaxation of tracheal muscle (bronchodilation) is seen. β2 agonists (e.g., dobutamine) are known in general to exhibit inotropic activity. In addition, racemic β2 agonists can cause angina, vertigo, central stimulation, insomnia, airway hyperreactivity (hypersensitivity), nausea, diarrhea, dry mouth and vomiting. As with other pharmaceuticals, β2 agonists sometimes cause systemic adverse effects such as weakness, fatigue, flushed feeling, sweating, unusual taste, hoarseness, muscle cramps and backaches.
Furthermore, patients have a tendency to develop a tolerance to the bronchodilating effect of the racemic mixture of formoterol. This is related to desensitization, one of the most clinically significant phenomena involving the beta-adrenergic receptor. It has been observed that patients in prolonged beta-agonist therapy have a tendency to increase the dosage of drug they use. This occurs because after prolonged administration, the beta receptor appears to become desensitized to the agonist, thus requiring larger doses of the compound to effect an equivalent physiological response.
The problem of desensitization is especially significant in the treatment of diseases involving bronchospasms, such as asthma. The treatment of asthma usually involves self-administration either orally or by aerosol, of beta-adrenergic agonists such as the racemic (R,R)/(S,S) mixture of formoterol. These agonists mediate bronchodilation and promote easier breathing. Asthmatic patients utilizing β2 agonists for a prolonged time gradually increase the self-administered dose in order to get a sufficient amount of bronchodilation and relief in breathing. As a result of this increased dosage, the agonist concentration builds to a sufficient level so as to enter the peripheral circulation where it acts on the beta receptors of the heart and vasculature to cause cardiovascular stress and other adverse effects.
Moreover, when administering the racemic mixture of formoterol by inhalation, due to the particle size and air flow distribution characteristics of the racemic mixture of formoterol, the distribution of the compound into the smaller bronchioles is limited, which results in a decreased effectiveness of the compound. It is therefore desirable to find a compound with the therapeutic characteristics of formoterol which would not have the above described disadvantages.